Neovascular diseases of the eye include diabetic retinopathy, age-related macular degeneration and neovasculature growth induced by angiogenic factors or resulting from tumor cells, themselves. Diabetic retinopathy is characterized by a number and variety of microvascular changes which can result ultimately in adverse visual changes and vision loss. In many cases the microvascular changes are due to or associated with upregulation of angiogenesis receptors and factors of ligands which lead to new vessel formation, changes in vascular permeability, and possibly other alterations in vessel morphology. These changes may lead to hemorrhage, edema, ischemia, and other problems resulting in vision dysfunction (see: Aiello et al., Diabetes Care, 21:143-156, 1998).
Treatments for the various forms of, and problems associated with, diabetic retinopathy include laser photocoagulation, vitrectomy, cryotherapy, and membranotomy. All of these clinical therapies and procedures are associated with problems and side effects. For example, the side effects and complications related to panretinal laser photocoagulation, the most common present treatment for diabetic retinopathy, include: decreased visual acuity, increased macular edema, transient pain, exudative retinal detachment, and inadvertent foveolar burns.
Age-related macular degeneration (“AMD”) is the leading cause of blindness in the United States among individuals 65 or older. One form of AMD is characterized by formation of choroidal neovessels which can lead to a number of pathologic conditions resulting in visual dysfunction and loss. As with diabetic retinopathy, angiogenesis plays a key role in the formation of these neovessels. The proliferation of choroidal neovessels associated with AMD can contribute to irreversible damage of photoreceptors. Thus, current treatment of AMD, like that of diabetic retinopathy, involves the use of laser photocoagulation. However, because photocoagulation relies upon the gross thermal destruction of the choroidal neovascular tissue, damage to the retina and surrounding choroidal tissue often results. Furthermore, recurrences after photocoagulation therapy are common. (see: Schmidt-Erfurth et al., Greafe's Arch Clin Exp Opthamol, 236:365-374, 1998).
As an alternative to photocoagulation, photodynamic therapy has been proposed as a means of treating this form of AMD (see: Strong et al., “Vision through photodynamic therapy of the eye,” U.S. Pat. Nos. 5,756,541 and 5,910,510; and Mori et al., “Photochemotherapeutical obstruction of newly-formed blood vessels,” U.S. Pat. No. 5,633,275). Photodynamic therapy (“PDT”), as taught in this prior art, is a two-step treatment process. PDT is performed by first administering a photosensitive compound systemically or topically, followed by illumination of the treatment site at a wavelength or waveband of light from a laser which closely matches the absorption spectra of the photosensitizer. In doing so, singlet oxygen and other reactive species are generated leading to a number of biological effects resulting in damage to the endothelial membranes and ultimately to clotting of the neovasculature.
Although this form of PDT represents an improvement over photocoagulation, clinical experience has established that the therapy must be repeated on a regular basis, typically every 3 months due to regrowth of the vessels (see: Schmidt-Erfurth et al.). The regrowth is believed to be due to upregulation of angiogenic factors and/or receptors secondary to the relative ischemia caused by the PDT treatment as outlined in the prior art. Clearly there is a need for a therapy which reduces the number of treatments which probably need to be performed for the rest of the patient's life.
In addition to neovascular tissue formation associated with diabetic retinopathy and age-related macular degeneration, the growth of new blood vessels are also associated with tumor formation in the eye, which results from two mechanisms: the stimulated growth of endothelial cells of existing blood vessels through angiogenesis; and a newly discovered vasculature resulting from highly malignant uveal melanomas, which develop in the eye, are full of networks of blood channels made by the melanoma cells themselves (Maniotis et al., American Journal of Pathology 155(3):739-52 (1999)). It may be that anti-angiogenic agents are ineffective in the treatment of such neovasculature arising not from endothelial cells, but from tumor cells such as those of malignant uveal melanomas.
Furthermore, because current PDT methods involve the systemic administration of untargeted photosensitive compounds or photosensitizers, the required dosages are relatively high which can lead to skin photosensitivity. The accumulation of photosensitizers in the skin is a property of all systemically administered sensitizers in clinical use. For example, clinically useful porphyrins such as Photophrin.RTM. (QLT, Ltd. brand of sodium porfimer) are associated with photosensitivity lasting up to 6 weeks. Purlytin.RTM., which is a purpurin, and Foscan.RTM., a chlorin, sensitize the skin for several weeks. Indeed, efforts have been made to develop photoprotectants to reduce skin photosensitivity (see: Dillon et al., Photochemistry and Photobiology, 48(2):235-238, 1988; and Sigdestad et al., British J. of Cancer, 74:S89-S92, 1996). In fact, PDT protocols involving systemic administration of photosensitizer require that the patient avoid sunlight and bright indoor light to reduce the chance of skin phototoxic reactions.
While there are reports in the scientific literature describing the use of ligand-receptor binding pairs, the literature is primarily drawn to the treatment of malignant tumor cells. There are a few reports that address the treatment of eye-related neovascular diseases such as diabetic retinopathy and AMD. However, either these reports fail to disclose the use of PDT at all or these reports fail to teach the use of such methods in conjunction with the targeting of blood vessels (see, for example: Savitsky et al., SPIE, 3191:343-353, 1997; Ruebner et al., SPIE, 2625: 328-332, 1996; Reno et al., U.S. Pat. No. 5,630,996; Casalini et al., J. Nuclear Med., 38(9):1378-1381, 1997; Griffiths, U.S. Pat. No. 5,482,698; and Mew et al., J. of Immunol., 130(3): 1473-1477, 1983). It should be noted that even though Strong et al. U.S. Pat. Nos. 5,756,541 and 5,910,510 suggest that a photoactive agent may be coupled to a specific binding ligand which may bind to a specific surface component of the target ocular tissue, there is little guidance provided to suggest appropriate ligands effective in such PDT methods.
Regarding light sources for PDT, high powered lasers are usually employed in order to shorten the procedure time (see: Strong et al., U.S. Pat. Nos. 5,756,541 and 5,910,510; and Mori et al., U.S. Pat. No. 5,633,275; see more generally, W. G. Fisher, et al., Photochemistry and Photobiology, 66(2):141-155, 1997).
However, the present art lacks an effective method of treating neovasculature diseases of the eye using a PDT methodology, which reduces damage to collateral or healthy tissue and which does not expose the tissue of the eye to intense laser light. The present art further teaches the need for recurrent treatment, the need for which is thought to arise, as discussed above, due to upregulation of angiogenic factors and/or receptors secondary to the relative ischemia caused by the PDT treatment as outlined in the prior art. Clearly there is a need for a therapy which reduces the number of treatments which probably need to be performed for the rest of the patient's life.
Citation of the above documents is not intended as an admission of any of the foregoing is pertinent prior art. All statements as to the date representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are incorporated in their entirety by reference herein.